Acute and chronic pancreatitis are major health-care problems in the United States causing years of pain and disability. Despite the impact of these diseases, mystery surrounds many of the predisposing causes and early molecular events. Furthermore, the devastating effects of acute pancreatitis and chronic pancreatitis, once established, cannot be reversed. We believe that in the future, advances in the treatment of pancreatic disease rest in the early identification of at-risk individuals as well as in the prevention of limitation of pancreatic injury. Thus, the goal of our program is to determine the molecular mechanisms that predispose to acute and chronic pancreatitis and to identify targets for disrupting pathophysiological processes. We believe that effective preemptive actions will prevent or limit pancreatic injury and thus, result in the reduction of he incidence and severity of acute and chronic pancreatitis. To understand the mechanisms of pancreatitis we will identify previously uncharacterized hereditary pancreatitis families and investigate several striking features of this disease including incomplete penetrance and the mechanisms causing pancreatitis with trypsinogen RR117H and N21I mutations. Answering this question may provide insight into the pathophysiology of acute and chronic pancreatitis and identify targets for new therapies, and help identify individuals at risk through genetic testing.